Elevated expression of TNFRSF4 impacts immune cell infiltration and gene mutation in hepatocellular carcinoma

Abstract

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, which makes prognostic prediction challenging.We aimed to investigate association of TNFRSF4 expression with the immune infiltration and gene mutation in HCC. METHODS: In this study, the expression profiles and corresponding clinical data of HCC patients were downloaded from the Cancer Genome Atlas (TCGA) database. Kaplan-Meier and Cox regression were used to evaluate the clinical value of TNFRSF4. ESTIMATE and CIBERSORT algorithms were applied to investigate the infiltration ratio of 22 immune cells. The WGCNA and LASSO COX algorithms were performed, establishing a prognostic risk model that was then validated by HCC samples from GEO. Finally, the effects on gene mutation occurring in HCC patients of TNFRSF4 expression and risk score were appraised. RESULTS: In HCC tissues, it was found the TNFRSF4 expression profile was significantly different with age, gender, tumor grade, disease stage, prominently affecting the survival outcome and prognosis of patients. Univariate and multivariate COX regression analysis suggested that TNFRSF4 was an independent prognostic marker. Samples of high/low expression of TNFRSF4 were screened for differential genes, and then the WGCNA and LASSO COX constructed a 13-gene signature, excellently dividing samples into hign/low risk groups. Compared with the low-risk group, the overall survival (OS) of high-risk group was markedly lower, with P< 0.0001. By ROC curve analysis, the predictive ability of the 13-gene signature was further confirmed. Both the high/low TNFRSF4 expression and the high/low risk score were demonstrated to exert effects on the frequency of gene mutation in HCC. CONCLUSIONS: As an independent prognostic marker of HCC, TNFRSF4 was found simultaneously to affect the immune infiltration of cells and the frequency of gene mutations.

Prognostic significance of TNFRSF4 expression and development of a pathomics model to predict expression in hepatocellular carcinoma

“…Our results demonstrated that elevated TNFRSF4 expression was associated with a significant reduction in OS in the HCC population. This finding supports previous research that has indicated TNFRSF4 expression as a prognostic marker in various cancers, including HCC [ 28 , 29 ]. The association between TNFRSF4 expression and OS remained significant even after adjusting for multiple clinical factors, indicating that TNFRSF4 expression can independently predict patient outcomes.…”

Transcriptomic Profiles Associated with Experimental Placebo Effects in Chronic Pain

“…40 TNFRSF4, known as OX40 or CD134 is expressed primarily on activated T cells and can activate the NF-kappa-B pathway by mediating TRAF2, TRAF5, PI3K/PKB, and NFAT pathways. 41 The most important function of TNFRSF4 is to enhance cellular division, proliferation, survival, and cytokine production of T cells by activating the pathways described above, with a potential role in immunotherapy. The PI3 gene encodes an elastase-specific inhibitor peptide against Gram-positive and Gram-negative bacteria, and fungal pathogens, and its expression is upregulated by both bacterial lipopolysaccharides and cytokines.…”

“…The expression of CCDC85B is regulated in a p53‐dependent manner (p‐53 has anti‐oncogenic actions blocking β‐catenin‐dependent gene expression in the nucleus) 40 . TNFRSF4 , known as OX40 or CD134 is expressed primarily on activated T cells and can activate the NF‐kappa‐B pathway by mediating TRAF2, TRAF5, PI3K/PKB, and NFAT pathways 41 . The most important function of TNFRSF4 is to enhance cellular division, proliferation, survival, and cytokine production of T cells by activating the pathways described above, with a potential role in immunotherapy.…”

Genome-Wide Detection and Analysis of Copy Number Variation in Anhui Indigenous and Western Commercial Pig Breeds Using Porcine 80K SNP BeadChip

“…TNFRSF4 is one of the major members of the TNF receptor-family member 4 (TN-FRSF4) and is mainly inducibly expressed in activated CD4+ and CD8+ cells [ 47 ]. TNFRSF4, combined with its ligand, can promote the proliferation of T cells, prevent the development of immune tolerance [ 48 ], and play an important role in the immune environment [ 49 ]. In our study, we found that TNFRSF4 was lost in WECP populations.…”